Hepatitis C virus (HCV) often causes chronic infection that affects over 200 million people worldwide. Chronic HCV infection is associated with fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The approved therapy for HCV infection is pegylated interferon-1 (IFN- 1) in combination with ribavirin that offers limited benefit depending on the genotype of the infecting virus. However, the molecular mechanisms underlying treatment failure remain unknown. Our long-term goal is to understand how HCV causes persistent infection at the molecular level, which will help in developing effective therapeutic modalities. Studies on HCV is challenging because of its limited growth in cell culture, and lack of a convenient animal model for virus infection and disease progression. We have recently shown that HCV infection in cell culture activates interferon beta (IFN-2) expression and induces autophagy. However, we do not fully understand how HCV blunts innate immune response and establishes chronic infection. We hypothesize that HCV interacts with cellular proteins and perturb their functions for establishment of persistent infection. Three complementary approaches will be used to test our hypothesis: Aim 1 will determine molecular processes by which HCV modulates intracellular IFN signaling pathway. Aim 2 will determine whether HCV impairs innate immunity by induction of autophagy. Finally, Aim 3 will examine intrahepatic innate immune response in HCV infected patients to correlate with treatment outcome. The results from our proposed studies will provide molecular mechanisms for viral persistence, and will aid in devising future therapeutic strategies for treatment of chronic HCV infection.